<i>CASP8</i> intronic expansion identified by poly-glycine-arginine pathology increases Alzheimer's disease risk.

ABSTRACT: Alzheimer's disease (AD) affects more than 10% of the population ≥65 y of age, but the underlying biological risks of most AD cases are unclear. We show anti-poly-glycine-arginine (a-polyGR) positive aggregates frequently accumulate in sporadic AD autopsy brains (45/80 cases). We hypothesize that these aggregates are caused by one or more polyGR-encoding repeat expansion mutations. We developed a CRISPR/deactivated-Cas9 enrichment strategy to identify candidate GR-encoding repeat expansion mutations directly from genomic DNA isolated from a-polyGR(+) AD cases. Using this approach, we isolated an interrupted (GGGAGA)_n intronic expansion within a SINE-VNTR-Alu element in CASP8 (CASP8-GGGAGA^EXP). Immunostaining using a-polyGR and locus-specific C-terminal a

SUBMITTER: Nguyen L 

PROVIDER: S-EPMC11848317 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature